Glycerine derivatives

ABSTRACT

Novel purine derivatives are described as agents for treating autoimmune diseases as well as a method of manufacture and pharmaceutical compositions as well as novel intermediates in the manufacture thereof.

This is a division of U.S. application Ser. No. 022,467, filed Mar. 6,1987, now U.S. Pat. No. 4,806,642, which is a continuation of U.S.application Ser. No. 657,211, filed Oct. 5, 1984, now abandoned, whichis a continuation-in-part of U.S. application Ser. No. 547,297, filedOct. 31, 1983, now abandoned.

SUMMARY OF THE INVENTION

The present invention relates to a compound of the formula ##STR1##wherein R₁ is OH or SH; R₂ is hydrogen, NHR in which R is hydrogen orCOR₆ where R₆ is alkyl of 1-4 carbon atoms, aryl or arylalkyl; R₃ isbromine or NHR where R is hydrogen or COR₆ ; X is O or S; R₄ is hydrogenor CH₂ OR₅ in which R₅ is hydrogen, alkyl of 1-8 carbon atoms, arylarylalkyl, ##STR2## or COR₆, or a pharmaceutically acceptable acid orbase addition salt thereof.

In a second generic aspect, the present invention relates to a compoundof the formula 1, wherein R₁ is OH or SH; R₂ is hydrogen or NHR in whichR is hydrogen or COR₆ where R₆ is alkyl of one to four carbon atoms,aryl or arylalkyl; R₃ is hydrogen; X is O or S; R₄ is alkyl of one toeight carbon atoms, aryl or arylalkyl, and R₅ is hydrogen, or apharmaceutically acceptable acid or base addition salt thereof.

In a third generic aspect, the present invention relates to a compoundof the formula 1, wherein R₁ is OH or SH; R₂ is hydrogen or NHR in whichR is hydrogen or COR₆ where R₆ is alkyl of one to four carbon atoms,aryl or arylalkyl; R₃ is hydrogen; X is O or S; R₄ is CH₂ OR₇ in whichR₇ is alkyl of one to eight carbon atoms, cycloalkyl of five to sevenring members, cycloalkylalkyl, aryl or arylalkyl, and R₅ is hydrogen, ora pharmaceutically acceptable acid or base addition salt thereof.

The present invention includes a method of manufacture, pharmaceuticalcomposition comprising an effective amount of a compound of the formula1 in all three generic aspects with a pharmaceutically acceptablecarrier, as well as a method of treatment of autoimmune diseases such asarthritis, systemic lupus erythematosus, inflammatory bowel diseases,transplantation, juvenile diabetes, myasthenia gravis, multiplesclerosis as well as viral infections and cancer by administering aneffective amount of a compound of the formula 1 in all three genericaspects in unit dosage form.

DETAILED DESCRIPTION

The term "alkyl of 1-8 carbon atoms" means a straight or branchedhydrocarbon chain up to 8 carbon atoms such as, for example, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary-butyl, oroctyl.

The term "cycloalkyl of five to seven ring members" means cyclopentyl,cyclohexyl, or cycloheptyl.

The term "cycloalkylalkyl" means a cyclopentyl, cyclohexyl, orcycloheptyl radical attached to an alkyl chain of up to four carbonatoms, straight or branched, such as for example, cyclohexylmethyl orcyclohexylethyl.

The term "aryl" includes unsubstituted and substituted aromatic ringsuch as, phenyl or phenyl substituted by halo, e.g., fluoro, chloro,bromo, or alkyl of 1-4 carbon atoms, such as methyl or ethyl, hydroxy,alkoxy of 1-4 carbon atoms, such as methoxy or ethoxy, ortrifluoromethyl.

The term "arylalkyl" means an aromatic ring attached to an alkyl chainof up to 4 carbon atoms, such as unsubstituted or substitutedphenylethyl or benzyl where the substituents on the aromatic ring may bethe same as defined above.

Pharmaceutically acceptable base salts of the phosphate ester, where R₅is ##STR3## are the alkali metals, ammonium or substituted ammoniumsalts, such as sodium, potassium, and ammonium salts. The base salts maybe prepared by standard methods known in the art.

Pharmaceutically acceptable acid addition salts are those derived frominorganic acids such as hydrochloric, sulfuric and the like, as well asorganic acids such as methanesulfonic, toluenesulfonic, tartaric acid,and the like. These salts may also be prepared by standard methods knownin the art.

Other pharmaceutically acceptable salts are those derived from inorganicbases such as sodium hydroxide, potassium hydroxide or ammoniumhydroxide or organic bases such as arginine, N-methyl glucamine, and thelike. These salts may also be prepared by standard methods known in theart.

A preferred embodiment of the present invention in its first genericaspect is a compound of formula 1 wherein R₁ is OH or SH; R₂ is hydrogenor NHR in which R is hydrogen or COR₆ where R₆ is alkyl of 1-4 carbonatoms or phenyl; R₃ is bromine or NH₂ ; X is O or S; R₄ is hydrogen orCH₂ OR₅ in which R₅ is hydrogen, alkyl of 1-8 carbon atoms, benzyl orphenyl, or a pharmaceutically acceptable acid addition or base salt.

Another preferred embodiment of the present invention in its firstgeneric aspect is a compound of formula 1 wherein R₁ is OH; R₂ ishydrogen or NH₂ ; R₃ is bromine or NH₂ ; X is O; R₄ is hydrogen or CH₂OR₅ in which R₅ is hydrogen or a pharmaceutically acceptable acidaddition or base salt.

Particular embodiments of the present invention in its first genericaspect include 2,8-diamino-9-[(2-hydroxyethoxy)methyl]-9H-purin-6-ol,2-[(2,8-diamino-6-hydroxy-9H-purin-9-yl)methoxy]-1,3-propanediol,2,8-diamino-1,9-dihydro-9-[[1-(hydroxymethyl)-2-phenoxyethoxy)methyl]-6H-purin-6-oneand2-[(2-amino-8-bromo-6-hydroxy-9H-purin-9-yl)methoxy]-1,3-propanediol.The latter compound is not only useful pharmacologically but is alsouseful as an intermediate for preparing certain compounds of the presentinvention.

A preferred embodiment of the present invention in its second genericaspect is a compound of formula 1, wherein R₁ is OH; R₂ is hydrogen orNHR in which R is hydrogen or COR₆ where R₆ is alkyl of one to fourcarbon atoms, phenyl or benzyl; R₃ is hydrogen; X is O; R₄ is alkyl ofone to eight carbon atoms, phenyl or benzyl, and R₅ is hydrogen, or apharmaceutically acceptable acid addition or base salt.

Another preferred embodiment of the present invention in its secondgeneric aspect is a compound of formula 1, wherein R₁ is OH; R₂ ishydrogen or NHR in which R is hydrogen or COR₆ where R₆ is methyl; R₃ ishydrogen; X is O; R₄ is alkyl of four to eight carbon atoms, phenyl orbenzyl, and R₅ is hydrogen or a pharmaceutically acceptable acidaddition or base salt.

Particular embodiments of the present invention in its second genericaspect include2-amino-1,9-dihydro-9-[[[1-(hydroxymethyl)hexyl]oxy]methyl]-6H-purin-6-oneand2-amino-1,9-dihydro-9[[[1-(hydroxymethyl)nonyl]oxy]methyl-6H-purin-6-one.The above compounds are not only useful pharmacologically but are alsouseful as intermediates for preparing certain compounds of formula 1 ofthe present invention in its first generic aspect.

A preferred embodiment of the present invention in its third genericaspect is a compound of formula 1, wherein R₁ is OH; R₂ is hydrogen orNHR in which R is hydrogen or COR₆ where R₆ is alkyl of one to fourcarbon atoms, phenyl or benzyl; R₃ is hydrogen; X is O; R₄ is CH₂ OR₇ inwhich R₇ is alkyl of one to eight carbon atoms, cycloalkyl of five toseven ring members, cycloalkylalkyl, phenyl or benzyl, and R₅ ishydrogen, or a pharmaceutically acceptable acid addition or base salt.

Another preferred embodiment of the present invention in its thirdgeneric aspect is a compound of formula 1, wherein R₁ is OH; R₂ ishydrogen or NHR in which R is hydrogen or COR₆ where R₆ is methyl; R₃ ishydrogen; X is O; R₄ is CH₂ OR₇ in which R₇ is alkyl of two to eightcarbon atoms, cyclopentyl, cyclohexyl, cyclopentylmethyl,cyclohexylmethyl, phenyl or benzyl, and R₅ is hydrogen, or apharmaceutically acceptable acid addition or base salt.

Particular embodiments of the present invention in its third genericaspect include2-amino-9[[2-(cyclohexylmethoxy)-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one;2-amino-9-[[2-(hexyloxy)-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one;2-amino-9-[[2-(heptyloxy)-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one;2-amino-1,9-dihydro-9-[[1-(hydroxymethyl)-2-(pentyloxy)ethoxy]methyl]-6H-purin-6-one;2-amino-1,9-dihydro-9-[[1-(hydroxymethyl)-2-(octyloxy)ethoxy]methyl]-6H-purin-6-one,and2-amino-1,9-dihydro-9-[[1-(hydroxymethyl)-2-(phenoxy)ethoxy]methyl]-6H-purin-6-one.

The compounds of formula 1 may be prepared according to the followingscheme: ##STR4##

The compounds of formula 2 above where R₁ =OH, R₂ =NH₂, X=O, R₄ =H orCH₂ OH may be prepared according to British Patent Specification1,567,671 or J. C. Martin, et al, in J Med Chem 26, 759 (1983). Theremainder of the compounds of formula 2 above used as starting materialsand final products are prepared according to the schemes 1 and 2.Treatment of a compound of formula 2 with N-bromosuccinimide in aceticacid, DMF or methanol produces a compound of formula 3 which whentreated with hydrazine hydrate gives the hydrazine of formula 4 ordirectly the 8-amino derivative of formula 5. The reaction of the8-bromo compound with hydrazine may or may not proceed entirely to the8-amino compound. Thus when the 8-hydrazine compound is obtained, it maybe further reacted with Raney nickel to allow the reduction to go tocompletion and afford the desired 8-amino compound. Compounds of formula5 wherein R₁, R₂, and R₄ have been defined according to compounds offormula 1 may be further converted by known methods to provide R₅substituents of formula 1 or, for example, where R₁ is OH, convertingsaid compound to a compound of formula 1 where R₁ is SH by known means.

The compounds of the present invention and of the formulae 1, 2, 3, 4,and 5, shown above, may also be prepared by the following schematicsequences of reaction steps as illustrated in Schemes 1 and 2. Thenumbers in parentheses toward the end of each reaction scheme correspondto the compounds of the present invention as defined above. A moredetailed description of the reaction steps is provided in the Examples.

In the preparation of compounds of the present invention and of theformulae 1 and 5, there are employed novel intermediates which are partof the present invention. These are compounds of the formula ##STR5##wherein Y is acetyloxy or chloro and R₇ is alkyl of one to eight carbonatoms, cycloalkyl of five to seven ring members, cycloalkylalkyl, arylor arylalkyl. Preferably, R₇ is alkyl of two to eight carbon atoms,cyclopentyl, cyclohexyl, cyclopentylmethyl, cyclohexylmethyl, phenyl orbenzyl. ##STR6##

The compounds of the present invention have been shown to exhibitsignificant enzyme inhibition activity and cytotoxic activity. In thepurine nucleoside phosphorylase (PNP-4) enzyme assay, total inhibitionwas achieved at a concentration less than about 300 micromoles oncertain compounds. The same compounds also were found by a standard test(Science, 214, 1137, 1981) to be selectively cytotoxic for T-cells inthe presence of 2'-deoxyguanosine at a similar concentration range. Forexample, 2,8-diamino-9-[(2-hydroxyethoxy)methyl)]-9H-purine-6-ol isselectively cytotoxic to T-cell at a concentration of about 30micromoles in the presence of 10 micromoles of 2'-deoxyguanosine.Similarly,2-[(2,8-diamino-6-hydroxy-9H-purin-9-yl)methoxy]-1,3-propanediol isselectively cytotoxic to T-cell at a concentration of about 7 micromolesin the presence of 10 micromoles of 2'-deoxyguanosine. Both compoundswere nontoxic to B-cell in the presence of the same amount of2'-deoxyguanosine. Since T-cells play a central role in immune response,use of the compounds of the invention is contemplated for theimmunoregulation of autoimmune disease such as rheumatoid arthritis,systemic lupus erythematosus, inflammatory bowel disease, cancer, andviral diseases, transplantation, juvenile diabetes, myasthenia gravis,and multiple sclerosis. The present invention thus includes compositionscontaining a compound of formula 1 in treating disease such asautoimmune disease characterized by abnormal immune response inwarmblooded animals. According to this aspect of the invention, theproperties of the compounds of the invention are utilized byadministering to a warm-blooded animal an effective amount of apharmaceutical composition containing as the active ingredient at leastabout 0.1 percent by weight, based on the total weight of thecomposition of at least one such compound of the invention.

Pharmaceutical compositions of the invention can be formulated in anysuitable way, preferably with an inert carrier for administrationorally, parenterally, ophthalmically, topically, or by suppository.

For example, the compounds of the present invention are formulated intodosage forms such as tablets or syrups by blending with an inertpharmaceutical carrier such as lactose or simple syrup by methods wellknown in the art. For injectionable dosage forms, they are formulatedwith vehicles such as water, peanut oil, sesame oil, and the like. Inthese dosage forms, the active ingredient is from about 0.05 grams to0.5 grams per dosage unit.

The present invention is further illustrated by way of the followingexamples.

EXAMPLE 1 2-Amino-8-bromo-9-[(2-hydroxyethoxy)methyl]-9H-purin-6-ol^(a)

N-bromosuccinimide (0.415 g; 2.3 mmol) is added to a solution ofacycloguanosine (0.5 g; 2.2 mmole) (prepared according to British Pat.No. 1,567,671) in acetic acid (7 ml) and the mixture stirred at roomtemperature for 20 hours. The solution is then diluted with water (20ml) and the precipitated product is filtered, washed, and trituratedwith hot water to give 0.25 g of white solid, mp>300° C.

EXAMPLE 1A

The procedure described in Example 1 is repeated to prepare thefollowing 8-bromo-9-substituted guanines starting from appropriate9-substituted guanines in each case using acetic acid, methanol or DMFas solvent:

2-amino-8-bromo-9-[[2-(heptyloxy)-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one,mp>250° C., dec;

2-amino-8-bromo-9-[[2-(hexyloxy)-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one,mp>250° C., dec;

2-amino-8-bromo-9-[[2-butoxy-1-(hydroxymethyl)ethoxy]methyl]-9H-purin-6-ol,mp>200° C.;

2-amino-8-bromo-1,9-dihydro-9-[[1-(hydroxymethyl)-2-(octyloxy)ethoxy]methyl]-6H-purin-6-one,mp 223°-226° C., dec;

2-amino-8-bromo-9-[[2-(hexyloxy)-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one,mp 212°-214° C.;

2-amino-8-bromo-9[[2-ethoxy-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one,mp 217°-219° C., dec;

2-amino-8-bromo-1,9-dihydro-9-[[1-(hydroxymethyl)-2-(pentyloxy)ethoxy]methyl]-6H-purin-6-one,mp>250° C., dec;

2-amino-8-bromo-9-[[2-(cyclohexylmethoxy)-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one,mp 210°-212° C. (dec);

2-amino-8-bromo-1,9-dihydro-9-[[1-(hydroxymethyl)-2-phenoxyethoxy]methyl]-6H-purin-6-one,mp 218°-219° C., dec;

2-amino-8-bromo-1,9-dihydro-9-[[2-(hydroxy)-1-[(4-methoxyphenoxy)methyl]ethoxy]methyl]-6H-purin-6-one;mp 205°-210° C., dec;

2-amino-8-bromo-1,9-dihydro-9-[[1-(hydroxymethyl)-2-(4-methylphenoxy)ethoxy]methyl]-6H-purin-6-one,mp 207°-208° C., dec;

2-amino-8-bromo-1,9-dihydro-9-[[2-(4-chlorophenoxy)-2-(hydroxymethyl)ethoxy]methyl]-6H-purin-6-one,and

2-amino-8-bromo-1,9-dihydro-9-[[[1-(hydroxymethyl)nonyl]oxy]methyl]-6H-purin-6-one,mp 211°-212° C., dec.

EXAMPLE 2 2,8-Diamino-9-[(2-hydroxyethoxy)methyl)]-9H-purin-6-ol

The crude 2-amino-8-bromo-9-[(2-hydroxyethoxy)methyl]-9H-purin-6-ol fromacycloguanosine (3.17 g; 0.14 mol) is suspended in water (10 ml) and 97%hydrazine (4 ml) is added to the mixture. The mixture is refluxed for 48hours, cooled and filtered to give a white solid (1.6 g) which istriturated with hot water (75 ml) to give the analytical sample (1.5 g),mp>300° dec.

EXAMPLE 32-[(2-Amino-8-bromo-6-hydroxy-9H-purin-9-yl)methoxy]-1,3-propanediol

N-bromosuccinimide (0.375 g; 2.1 mmol) is added to a solution of9'-[(1,3-dihydroxy-2-propoxy)methyl]guanine (0.5 g; 1.9 mmole) [preparedaccording to J. C. Martin; C. A. Dvorak, D. F. Smee, T. R. Matthews, andJ. P. H. Verheyden, J Med Chem 26, 759-761 (1983)] in acetic acid (7ml). The suspension is stirred for 1.5 hours at room temperature andthen diluted with water (60 ml). The aqueous solution is concentratedand the residue is recrystallized from water to give 0.44 g of theproduct; mp>300° dec.

EXAMPLE 42-[(2,8-Diamino-6-hydroxy-9H-purin-9-yl)methoxy]-1,3-propanediol

A mixture of2-[(2-amino-8-bromo-6-hydroxy-9H-purin-9-yl)methoxy]-1,3-propanediol(13.7 g; 41 mmole) and 97% hydrazine (6.07 ml) in water (300 ml) isheated to reflux for 48 hours. At the end of this time, the solution iscooled and filtered to give 9.15 g of crude solid. The crude product issuspended in water (120 ml) and Raney nickel (9 g) is added. The mixtureis heated at reflux for 6 hours, filtered hot and cooled. The crystalsare collected and dried to give 7.15 g of the product, mp>280° dec.

EXAMPLE 4A

The procedure described in Example 4 is repeated to prepare thefollowing 8-amino-9-substituted guanines starting from appropriate8-bromo-9-substituted guanines in each case using methoxyethanol as acosolvent as necessary to make a homogeneous reaction mixture:

2,8-diamino-9-[[2-ethoxy-1-(hydroxymethyl)ethoxy]methyl]-9H-purin-6-ol,mp>220° C., dec;

2,8-diamino-9-[[2-(hexyloxy)-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one,mp>265° C., dec;

2,8-diamino-9-[[2-butoxy-1-(hydroxymethyl)ethoxy]methyl]-9H-purin-6-ol,mp>240° C., dec;

2,8-diamino-1,9-dihydro-9-[[1-(hydroxymethyl)-2-(pentyloxy)ethoxy]methyl]-6H-purin-6-one,mp 274°-277° C., dec;

2,8-diamino-9-[[2-(heptyloxy)-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one,mp>260° C., dec;

2,8-diamino-9-[[2-(hexyloxy)-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one,mp 260°-265° C., dec;

2,8-diamino-9-[[2-(cyclohexylmethoxy)-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one,mp 242°-247° C., dec;

2,8-diamino-1,9-dihydro-9-[[1-(hydroxymethyl)-2-(octyloxy)ethoxy]methyl]-6H-purin-6-one,mp>265° C., (dec);

2,8-diamino-1,9-dihydro-9-[[1-(hydroxymethyl)-2-phenoxyethoxy]methyl]-6H-purin-6-one,mp 265°-271° C., dec;

2,8-diamino-1,9-dihydro-9-[[2-hydroxy-1-[(4-methoxyphenoxy)methyl]ethoxy]methyl]-6H-purin-6-one;

2,8-diamino-1,9-dihydro-9-[[1-(hydroxymethyl)-2-(4-methylphenoxy)ethoxy]methyl]-6H-purin-6-one;mp>250° C., dec;

2,8-diamino-1,9-dihydro-9-[[2-(4-chlorophenoxy)-1-(hydroxymethyl)ethoxy]methyl]-6H-purin-6-one,and

2,8-diamino-1,9-dihydro-9-[[[1-(hydroxymethyl)nonyl]oxy]methyl]-6H-purin-6-one.

EXAMPLE 59-[[2-Benzyloxy-1-(benzyloxymethyl)-ethoxy]methyl]-8-hydrazine-guanine

A mixture of 9-[[2-benzyloxy-1-(benzyloxymethyl)-ethoxy]methyl]guanine(2.1 g) [prepared according to K. K. Ogilvie, V. O. Cheriyan, B. K.Radatus, K. O. Smith, K. S. Galloway, and W. L. Kennell, Can J Chem, 60,3005 (1982)] and N-bromosuccinimide (0.94 g) in acetic acid (21 ml) isstirred overnight and then is diluted with water and extracted withchloroform. The chloroform extract is dried and concentrated to give 2.3g of yellow oil. The crude oil is suspended in ethanol (100 ml) andtreated with 95% hydrazine. The solution is heated to reflux for 24hours. The reaction mixture is then cooled and the product (0.75 g)filtered and dried, mp>210° dec.

EXAMPLE 68-Amino-9-[[2-benzyloxy-1-(benzyloxymethyl)-ethoxy]methyl]-guanine

A mixture of9-[[2-benzyloxy-1-(benzyloxymethyl)ethoxy)methyl]-8-hydrazine-guanine(0.45 g; 0.98 mmol), water (40 ml), ethanol (40 ml), ammonium hydroxide(20 ml) and Raney nickel (1 g) is heated to reflux for 24 hours. Thecatalyst is filtered off and the filtrate concentrated to a solid whichis recrystallized from ethanol to give 0.16 g of analytical sample, mp255°-260° dec.

EXAMPLE 7N-[9-[[1-(Butoxymethyl)-2-(phenylmethoxy)ethoxy]methyl]-6-hydroxy-9H-purin-2-yl]acetamide

Dry HCl (g) is bubbled into a stirred mixture of paraformaldehyde (1.45g, 0.048 mol) and 1-butoxy-3-(phenylmethoxy)-2-propanol (5.0 g, 0.021mol) in methylene chloride (57 ml) at 0° C. until all the solid isdissolved. The resulting solution is stored at 0° C. for 16 hours, driedover MgSO₄, and then evaporated to give chloromethyl glycerol ether as avery unstable clear oil. The clear oil is then added dropwise to astirred mixture of potassium acetate (5.0 g, 0.051 mol) in acetone (60ml). The mixture is stirred for 16 hours at room temperature and thenfiltered and evaporated. The residual oil is dissolved in toluene,washed with saturated NaHCO₃ and water, dried, and evaporated to givethe acetoxy derivative as an oil (5.6 g) which is immediately used forcondensation with diacetylguanine.

A mixture of diacetylguanine (4.6 g, 0.0195 mol) and crude acetoxyderivative from above (5.6 g), p-toluene sulfonic acid (43 mg) andsulfolane (5 ml) is heated to 95° C. under nitrogen atmosphere for 72hours. At 24 hours and 48 hours, additional amounts of p-toluenesulfonic acid (20 mg each) are added. After 72 hours, the mixture iscooled, diluted with toluene and filtered. The filtrate is concentrated,chromatographed, and recrystallized from toluene to provide the desiredproduct (1.33 g), mp 139°-141° C.

EXAMPLE 8

The procedure described in Example 7 is repeated to prepare thefollowing guanine-2-acetamide derivatives, starting from diacetylguanineand appropriate 1-(alkoxy or alkyl or substitutedphenoxy)-3-(phenylmethoxy)-2-propanols in each case.

N-[6,9-dihydro-9-[[1-[(octyloxy)methyl]-2-(phenylmethoxy)ethoxy]methyl]-6-oxo-1H-purin-2-yl]-acetamide,mp 127°-132° C.;

N-[6,9-dihydro-6-oxo-9-[[1-(phenoxymethyl)-2-(phenylmethoxy)ethoxy]methyl]-1H-purin-2-yl]-acetamide,mp 144°-146° C., and

N-[9-[[1-(ethoxymethyl)-2-(phenylmethoxy)ethoxy]methyl]-6,9-dihydro-6-oxo-1H-purin-2-yl]acetamide,mp 131°-133° C., dec.

EXAMPLE 92-Amino-9-[[2-butoxy-1-(hydroxymethyl)ethoxy]methyl]-9H-purin-6-ol

A mixture ofN-[9-[[1-(butoxymethyl)-2-(phenylmethoxy)ethoxy]methyl]-6-hydroxy-9H-purin-2-yl]acetamide(1.15 g, 25.9 mmol), 20% palladium on carbon (0.2 g), cyclohexene (20ml), and ethanol (10 ml) is heated at reflux under N₂. After 8 and 20hours, additional amounts of catalyst (0.1 g) are added. After 36 hours,the solution is cooled, filtered through celite, and the filter cake iswashed with DMF/ethanol. The filtrates are combined, refiltered andconcentrated. The residue is mixed with aq. methyl amine (20 ml) and themixture is heated at reflux for two hours, filtered and concentrated.The residue is recrystallized from water to give the desired product(0.7 g), mp 208°-211° C.

EXAMPLE 10

The procedure described in Example 9 is repeated to prepare thefollowing 9-substituted guanine derivatives, starting fromN-[9-substituted-6-hydroxy-9H-purin-2-yl]acetamides in each case.Cyclohexene and cyclohexadiene can either be used in the transferhydrogenation reaction:

2-amino-9-[[2-ethoxy-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one,mp 206°-209° C.;

2-amino-1,9-dihydro-9[[1-(hydroxymethyl)-2-phenoxyethoxy]methyl]-6H-purin-6-one,mp 195°-198° C., and

2-amino-1,9-dihydro-9-[[1-(hydroxymethyl)-2-(octyloxy)ethoxy]methyl]-6H-purin-6-one,mp 227°-230° C.

EXAMPLE 112-Amino-9-[[1-[(heptyloxy)methyl]-2-(phenylmethoxy)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one

A mixture of 2-amino-6-chloropurine (Aldrich Chemical Co.) 11.2 g, 0.066mol) hexamethyldisilazane (160 ml), and ammonium sulfate (1.09 g) isrefluxed for 2.5 hours and then cooled, concentrated and pumped todryness. The residue is dissolved in dry toluene (210 ml) and is treatedwith Hg(CN)₂. The mixture is heated to 80° C. and a solution of2-(chloromethoxy)-1-(heptyloxy)-3-(phenylmethoxy)propane (prepared from1-(heptyloxy)-3-(phenylmethoxy)-2-propanol (19 g, 0.068 mol),paraformaldehyde (4 g) and dry HCl (g) in CH₂ Cl₂ (160 ml) as describedin the first part of Example 7, in toluene (210 ml) is added to thesolution and heated to 80°-85° C. for 2.5 hours. The mixture is cooled,concentrated, and diluted with CH₂ Cl₂ (1.0 L) and is allowed to standovernight. The CH₂ Cl₂ solution is filtered, washed with 30% KI, 10%potassium carbonate solution and water. The organic layer is dried andconcentrated. The residue is chromatographed over silica gel columnusing a high pressure liquid chromatographic instrument (Waters Prep500). The column is eluted with ethyl acetate and hexane (1:1) to givethe condensation product (i.e., chloropurine drivative) (6.45 g) whichis hydrolysed as follows.

A mixture of the above chloropurine derivative (6.42 g, 0.0139 mol)methanol (150 ml) and sodium methoxide (3 g, 0.056 mol) is treated withmercaptoethanol (4.4 ml) and water (0.26 ml). The mixture is then heatedto reflux under nitrogen for two hours and then an additional amount ofsodium methoxide (1.9 g) is added. The reaction mixture is heated toreflux for an additional 4.0 hours, cooled, and concentrated to about 50ml. The concentrate is diluted with water (120 ml) and the solution isacidified to pH 6.0. The solid precipitate is filtered, washed withwater, and dried. The crude product is then recrystallized frommethanol/water to give an analytical sample (4.25 g), mp 185°-187° C.

EXAMPLE 12

The procedure described in Example 11 is repeated to prepare thefollowing 9-substituted guanines starting from 2-amino-6-chloropurineand appropriate 1-(alkoxy or substituted phenoxy oralkyl)-3-(phenylmethoxy)-2-propanols in each case:

2-amino-9-[1-[(cylcohexylmethoxy)methyl]-2-(phenylmethoxy)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one,mp 198°-201° C.;

2-amino-9-[1-[(hexyloxy)methyl]-2-(phenylmethoxy)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one;mp 192°-194° C.

2-amino-1,9-dihydro-9-[1-[(pentyloxy)methyl]-2-(phenylmethoxy)ethoxy]methyl]-6H-purin-6-one,mp 192°-194° C.;

2-amino-1,9-dihydro-9-[[-1-[(octyloxy)methyl]-2-(phenylmethoxy)ethoxy]methyl]-6H-purin-6-one,mp 184°-186° C.;

2-amino-1,9-dihydro-9-[1-(phenoxy)methyl)-2-(phenylmethoxy)ethoxy]methyl]-6H-purin-6-one;

2-amino-1,9-dihydro-9-[[[1-[(phenylmethoxy)methyl]hexyl]oxy]methyl-6H-purin-6-one,mp 206°-208° C.;

2-amino-1,9-dihydro-9-[[[1-[(phenylmethoxy)methyl]nonyl]oxy]methyl-6H-purin-6-one,mp 205°-207° C.;

2-amino-9-[1-[(4-chlorophenoxy)methyl]-2-[phenylmethoxy]ethoxy]methyl]-1,9-dihydro-6H-purin-6one,mp>210° C.;

2-amino-1,9-dihydro-9-[[1-[(4-methoxyphenoxy)methyl]-2-[phenylmethoxy]ethoxy]methyl]-6H-purin-6-one,mp 150°-156° C., and

2-amino-1,9-dihydro-9-[[1-[(4-methylphenoxy)methyl]-2-[phenylmethoxy]ethoxy]methyl]-6H-purin-6-one,mp 198°-200° C.

EXAMPLE 132-Amino-9-[[2-(heptyloxy)-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one

A mixture of2-amino-9-[1-[(heptyloxy)methyl]-2-(phenylmethoxy)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one(3.9 g, 8.97 mmol), ethanol (200 ml), cyclohexadiene (87 ml, 92.3 mmol),and 20% palladium on charcoal (1.5 g) is heated to reflux under nitrogenatmosphere. After seven hours an additional amount of 20% palladium oncharcoal (0.5 g) is added and the mixture is heated to reflux for atotal of 18 hours. The mixture is filtered hot and then allowed to cool.The solid formed is collected and dried to give the desired purine (1.95g), mp 224°-225° C.

EXAMPLE 14

The procedure described in Example 13 is repeated to prepare thefollowing 9-substituted guanines starting from appropriate phenylmethoxyderivatives described in Example 11 and 12.

2-amino-1,9-dihydro-9-[[[1-(hydroxymethyl)hexyl]oxy]methyl]-6H-purin-6-one,mp 228°-229° C.;

2-amino-1,9-dihydro-9-[[[1-(hydroxymethyl)nonyl]oxy]methyl]-6H-purin-6-one,mp>250° C., dec;

2-amino-9-[[2-(ethoxy)-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one,mp 206°-209° C.;

2-amino-9-[[2-(butoxy)-1-(hydroxymethyl)ethoxy]methyl]-9H-purin-6-ol, mp208°-211° C.;

2-amino-9-[[2-(hexyloxy)-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one;

2-amino-1,9-dihydro-9-[[1-(hydroxymethyl)-2-(penyloxy)ethoxy]methyl]-6H-purin-6-one,mp 218°-220° C.;

2-amino-1,9-dihydro-9-[[1-(hydroxymethyl)-2-(octyloxy)ethoxy]methyl]-6H-purin-6-one,mp 227°-230° C.;

2-amino-9-[[2-(cyclohexylmethoxy)-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purine-6-one,mp>260° C., dec;

2-amino-1,9-dihydro-9-[[1-(hydroxymethyl)-2-phenoxyethoxy]methyl]-6H-purin-6-one,mp 195°-198° C.;2-amino-1,9-dihydro-9-[[1-(hydroxymethyl)-2-(4-methylphenoxy)ethoxy]methyl]-6H-purin-6one,mp 206°-208° C.;

2-amino-1,9-dihydro-9-[[2-(hydroxy-1-[(4-methoxyphenoxy)methyl]ethoxy]methyl]-6H-purin-6-one,mp 210°-217° C., dec, and

2-amino-9-[[2-(4-chlorophenoxy)-1-(hydroxymethyl)ethoxy]methyl]-1,9-dihydro-6H-purin-6-one,

Synthesis of Starting Materials EXAMPLE A1-Butoxy-3-(phenylmethoxy)-2-propanol

n-Butanol (2.5 ml, 27 mmol) is added to a suspension of sodium hydride(50% in mineral oil; 1.3 g, 27 mmol) in DMF (5 ml) and the mixture isthen heated to 80° C. for 1.0 hours when all the sodium hydride isconsumed. A solution of 2,3-epoxypropyl benzyl ether (benzylglycidylether*) (4.52 g, 27 mmol) in DMF (5 ml) is added slowly to then-butoxide solution. The mixture is then heated to 80° C. for 16 hours,diluted with water and extracted with ether. The ether layer is driedand concentrated to give an oil which is distilled to provide thedesired product (3.1 g), bp 125°-130°/0.8-0.5 mm.

EXAMPLE B

The procedure described in Example A is repeated to prepare thefollowing 1-alkoxy or aryloxy-3-(phenylmethoxy)-2-propanols, startingfrom appropriate alkanols or phenols in each case.

1-(ethoxy)-3-(phenylmethoxy)-2-propanol, bp 92°-99° C./0.25-0.3 mm;

1-(pentyloxy)-3-(phenylmethoxy)-2-propanol, bp 115°-118° C./0.3 mm;

1-(hexyloxy)-3-(phenylmethoxy)-2-propanol, bp 123°-125° C./0.12 mm;

1-(heptyloxy)-3-(phenylmethoxy)-2-propanol, bp 141° C./0.36 mm, and

1-(octyloxy)-3-(phenylmethoxy)-2-propanol, bp 150°-155° C./0.7 mm.

EXAMPLE C 1-(Phenylmethoxy)-2-decanol

Benzyl alcohol (108 g, 1.0 mol) is added to a suspension of 50% sodiumhydride-mineral oil (48 g, 1.0 mol) in DMF (200 ml) at room temperature.The mixture is then heated to 80° C. for two hours. A solution of1,2-epoxydecane* (85 ml) in DMF (50 ml) is added slowly to the sodiumsalt over 30 minutes and the mixture is then heated at 80° C. for 20hours. The reaction mixture is cooled, diluted with water, neutralizedwith acetic acid, and extracted with ether. The ether extract isconcentrated to give an oil which is distilled to give the desiredproduct (131 g), bp 178°-180° C./4 mm.

EXAMPLE D

The procedure described in Example C is repeated to prepare thefollowing 1-(phenylmethoxy)alkanols, starting from appropriate1,2-epoxides in each case.

1-(cyclohexylmethoxy)-3-(phenylmethoxy)-2-propanol, bp 136°-139°C./0.24-0.22 mm;

1-(phenylmethoxy)-2-heptanol, bp 125°-130° C./3-5 mm;

1-(phenoxy)-3-(phenylmethoxy)-2-propanol, bp 148°-157° C./0.32 mm;

1-(4-methylphenoxy)-3-(phenylmethoxy)-2-propanol, bp 194° C./2 mm;

1-(4-methoxyphenoxy)-3-(phenylmethoxy)-2-propanol, bp 175°-184° C./0.4mm, and

1-(4-chlorophenoxy)-3-(phenylmethoxy)-2-propanol, bp 188°-190°C./1.2-1.3 mm.

We claim:
 1. A compound of the formula ##STR7## wherein Y is acetyloxyor chloro and R₇ is alkyl of one to eight carbon atoms, cyclopentyl,cyclohexyl, cyclopentylmethyl, or cyclohexylmethyl.